Glycopyrronium bromide (Glycopyrrolate, US Pharmacopeia) is the higher melting (193.2° C.-194.5° C.) of two possible diastereoisomeric racemates, i.e. the erythro racemate. Glycopyrronium bromide is manufactured by the method disclosed in U.S. Pat. No. 2,956,062, utilizing N-methylpyrrolidin-3-ol (NMP) and methyl hydroxycyclopentylmandelate (MCPM), as follows:

The initial product from the methylation reaction in methyl ethyl ketone (MEK; stage 3) is isolated as an approximately 50:50 mixture of the two possible pairs of diastereoisomers. In order to obtain the desired drug, i.e. the racemic mixture of the R,S and S,R pair of diastereoisomers, the R,R/S,S pair is removed by recrystallising the crude product from a mixture of methanol and MEK.
In the established manufacturing process, there is no provision to control the particle size of the drug substance. The large and inconsistent particle size produces a physically unstable drug substance following micronisation. Material is difficult to formulate into a drug product suitable for inhalation.
Further, apart from controlling the melting point, the US Pharmacopeia makes no provision for the determination of the amount of the R,R and S,S diastereoisomeric pair in the active pharmaceutical ingredient.
Commercially available MCPM may contain high levels of impurities. These impurities react competitively in stage 2, to produce high levels of carried through impurities in glycopyrronium base, and then in the final salt.